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Anti-tumor and immunomodulatory activity of the aqueous extract of Sarcodon imbricatus in vitro and in vivo

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Abstract

Sarcodon imbricatus (S. imbricatus), a well-known edible mushroom, is one of the most commonly consumed wild mushrooms in China because of its nutritional value. Previous studies have demonstrated that S. imbricatus has immunoregulatory activity. We previously described the potential anti-tumor activity of several types of mushrooms, including S. imbricatus. In this study, the results demonstrate that an aqueous extract of S. imbricatus (SIE) effectively inhibits the growth, migration, and invasion properties of breast cancer cells in vitro and reduces tumor growth in vivo. In addition, the SIE increased serum concentrations of interleukin (IL)-2, IL-6 and tumor necrosis factor-α, natural killer cell activity and the viability of splenocytes and reduced the expression of programmed cell death-Ligand 1 (PD-L1) in 4T1 tumor-bearing mice. Collectively, these results are the first demonstration that the SIE has anti-tumor and immunomodulatory effects in the 4T1 mouse breast cancer model. These findings provide a scientific rationale for the potential therapeutic use of S. imbricatus in breast cancer patients.

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... In China this species is also known as "black tiger's paw" (Marcotullio 2011). In relation to this, S. imbricatus, a rare mushroom, which is edible when young, and is one of the most commonly consumed wild mushrooms in China based on its nutritional values (Tan et al. 2020). In general, S. imbricatus contains 93.89 ± 0.00 g/100 g of fresh weight moisture, 3.38 ± 0.03 g/100 g f.w. ...
... Numerous studies have confirmed the antifatigue (Wang et al. 2018a), antimicrobial (Sułkowska-Ziaja et al. 2011Nikolovska Nedelkoska et al. 2013), antioxidant (Barros et al. 2007b;Marcotullio et al. 2008;Ozen and Türkekul 2010;Wang et al. 2018a), antitumor (Sułkowska-Ziaja et al. 2012Zhang et al. 2019;Tan et al. 2020), and immunomodulatory (Tan et al. 2020) biological activities of S. imbricatus. In addition, Thu et al. (2020) summarized that polysaccharides isolated from S. imbricatus have demonstrated to possess antibacterial, anti-myelosuppressive, and immunomodulatory activities. ...
... Numerous studies have confirmed the antifatigue (Wang et al. 2018a), antimicrobial (Sułkowska-Ziaja et al. 2011Nikolovska Nedelkoska et al. 2013), antioxidant (Barros et al. 2007b;Marcotullio et al. 2008;Ozen and Türkekul 2010;Wang et al. 2018a), antitumor (Sułkowska-Ziaja et al. 2012Zhang et al. 2019;Tan et al. 2020), and immunomodulatory (Tan et al. 2020) biological activities of S. imbricatus. In addition, Thu et al. (2020) summarized that polysaccharides isolated from S. imbricatus have demonstrated to possess antibacterial, anti-myelosuppressive, and immunomodulatory activities. ...
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Sarcodon imbricatus (L.) P. Karst. - BANKERACEAE Yusufjon Gafforov, Milena Rašeta, Sylvie Rapior, Manzura Yarasheva, Muhammad Zafar et Li-Wei Zhou. Sarcodon imbricatus (L.) P. Karst. - BANKERACEAE. Pages 1401-1415. doi:10.1007/978-3-031-23031-8_123 ; hal-04373902v1 ; hal-04385178v1
... Rich in essential proteins, polysaccharides, sterols, and triterpenoids, Trametes versicolor exhibits a broad spectrum of pharmacological activities, including antioxidant, immune-modulating, and anticancer effects. Among its most studied components are polysaccharopeptides (PSP) and polysaccharide-K (PSK), both of which have been evaluated in clinical settings for their anticancer potential (63,64). PSK, in particular, has been widely used as an adjunct therapy in cancer treatment, especially in Japan. ...
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Background: Cancer remains one of the most significant global health concerns, contributing to high morbidity and mortality rates. Conventional treatments such as chemotherapy, radiation therapy, and targeted therapies are widely used but often come with significant limitations, including severe side effects, resistance development, and compromised quality of life. The search for safer and more effective complementary therapies has led to growing interest in natural compounds with anticancer potential. Medicinal mushrooms have long been valued in traditional medicine for their nutritional and therapeutic properties, offering a promising alternative for cancer prevention and treatment.
... Moreover, a recent study demonstrated that an aqueous extract derived from shingled hedgehog (Sarcodon imbricatus) successfully suppressed the proliferation, movement, and invasive characteristics of breast cancer cells in vitro and also resulted in reduced tumor growth in living organisms. Additionally, this extract caused enhanced expression of PD-L1 and improved viability of NK cells [15]. In addition, Xue et al. discovered that a triterpenoid called EAe, derived from the king trumpet mushroom (Pleurotus eryngii), effectively suppressed the proliferation of the MCF-7 cell line with an EC50 value of 298 µg/mL. ...
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For centuries, humans have used mushrooms as both food and pro-health supplements. Mushrooms, especially those related to the functions of the human immune system, are rich in dietary fiber, minerals, essential amino acids, and various bioactive compounds and have significant health-promoting properties. Immunoregulatory compounds in mushrooms include lectins, terpenes, terpenoids, polysaccharides, and fungal immunomodulatory proteins (FIPs). The distribution of these compounds varies from one species of mushroom to another, and their immunomodulatory activities depend on the core structures and chemical modifications in the composition of the fractions. In this review, we describe active compounds from medical mushrooms. We summarize potential mechanisms for their in vitro and in vivo activities and detail approaches used in developing and applying bioactive compounds from mushrooms. Finally, we discuss applications of fungal peptides and highlight areas that require improvement before the widespread use of those compounds as therapeutic agents and explore the status of clinical studies on the immunomodulatory activities of mushrooms and their products, as well as the prospect of clinical application of AMPs as ‘drug-like’ compounds with great potential for treatment of non-healing chronic wounds and multiresistant infections.
... Sarcodon and Hydnellum species are common in markets in Sichuan and Yunnan Provinces in Southwest China, and they are of important economic value to the local people (Fig. 1). In addition, some species of the two genera, including S. imbricatus and S. leucopus, are reputed to have important medicinal functions (Ma et al. 2014;Tan et al. 2020). In the present study, the species diversity of the two genera marketed in Southwest China was analyzed based on morphological characters and DNA sequences (ITS, RPB2 and nLSU). ...
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Sarcodon and Hydnellum are two ectomycorrhizal genera of important ecological and economic value in Southwest China, and they are common in the free markets in this region. It was estimated that more than 1,500 tonnes of them were sold as edible per year, but there was little information about the taxonomic placements of these edible mushrooms sold in the markets. Traditional concepts of the two genera have also been challenged recently, and circumscription of Sarcodon and the informally defined clade “Neosarcodon” remained unresolved. In the present study, specimens collected in the field and purchased from the markets in Southwest China were analyzed based on morphological characters and DNA sequences. Phylogeny of the traditional Sarcodon s. lat. and Hydnellum s. lat. was reconstructed from the combined internal transcribed spacer (ITS), nuclear large ribosomal subunit (nLSU) and RNA polymerase II second largest subunit (RPB2) dataset based on expanded samples to reevaluate the taxonomic placements of the two genera. In the present molecular analyses, four distinct clades were recovered and strongly supported: Hydnellum, Neosarcodon, Phellodon and Sarcodon. Neosarcodon is formally introduced as a generic name to include nine species previously placed in Sarcodon, and the delimitation of Sarcodon is revised based on phylogenetic and morphological studies. Phylogenetic analyses also revealed an unexpected species diversity (17 phylogenetic species) of Sarcodon and Hydnellum in the markets; nine phylogenetic species of Sarcodon and eight of Hydnellum were uncovered from the samples collected in the markets. Eight species were resolved in the traditional S. imbricatus complex, with S. imbricatus s.str. being the most common edible stipitate hydnoid fungal species. Three of the edible Hydnellum species (H. edulium, H. subalpinum, and H. subscabrosellum), and five separated from the S. imbricatus complex (Sarcodon flavidus, S. giganteus, S. neosquamosus, S. nigrosquamosus, and S. pseudoimbricatus), are described as new. Three new Chinese records (H. illudens, H. martioflavum, and H. versipelle), and the notable S. imbricatus and S. leucopus are also reported.
... Grifola frondosa, Morchella esculenta, and Sarcodon imbricatus are edible mushrooms with excellent taste, aroma, and various reported therapeutic effects. [30][31][32] A major physiologically active polysaccharide substance extracted from G. frondosa displays excellent antitumor, immunomodulatory, and antioxidant activities. 32 In particular, this polysaccharide reportedly exhibits an excellent antiviral efficacy against hepatitis B virus (HBV), enterovirus 71 (EV71), herpes simplex virus type 1 (HSV-1), and human immunodeficiency virus (HIV). ...
Article
Coronaviruses (CoV) are among the major viruses that cause common cold in humans. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a high-risk human pathogen that derived from bat coronaviruses, although several other animals serve as CoV hosts, contributing to human infection. As the human activity area expanded, viruses previously prevalent only in animals mutated and became threats to humans as well, leading to worldwide epidemics. Therefore, controlling CoV infections in animals is essential to prevent CoV-related human infections. Feline coronavirus (FCoV) could be reportedly used as an alternative model for SARS-CoV-2. Traditionally, mushrooms are not only foods but are also consumed to prevent diseases. Importantly, certain edible and medicinal mushrooms display antibacterial and antiviral effects against respiratory pathogens; therefore, they could be tested as potential coronavirus treatment agents. In this study, we investigated if wild forest mushrooms with various reported physiological activities could exhibit an antiviral activity against CoV, using FCoV as a SARS-CoV-2 model infecting Crandell Rees feline kidney cells. We measured the antiviral activity of 11 wild mushrooms overall and our results demonstrated that Pleurotus ostreatus and Phallus luteus displayed the highest antiviral efficacy of 55.33%, followed by Tricholoma bakamatsutake at 43.77%. Grifola frondosa, Morchella esculenta , and Sarcodon imbricatus exhibited mild efficacy of 29.21%. We also tested Amanita caesareoides, Marasmius siccus, Pachyma hoelen, Phallus rubrovolvata , and Sparassis latifolia but could not detect any antiviral activity in their case. Our study confirms that wild forest mushrooms could be used as potential functional foods or pharmacological materials against coronavirus.
... The polysaccharide isolated from Sarcodon imbricatus not only regulates immunity and has some anticancer e cacy but also signi cantly enhances the immune activity of the hematopoietic system [42,43]. Although we expected to have high resistance to the in uenza virus, its e cacy was relatively low. ...
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Background: Oseltamivir is the most commonly used antiviral drug for the treatment and prevention of influenza. However, there are growing concerns about its use due to the risk of psychiatric side effects. Methods: Eleven species of edible medicinal mushrooms (Pleurotus ostreatus, Phallus rubrovolvata, Phallus luteus, Morchella esculenta, Grifola frondosa, Sarcodon imbricatus, Tricholoma bakamatsutake, Pachyma hoelen, Sparassis latifolia, Amanita caesareoides, and Marasmius siccus) were collected from forests in Korea to evaluate their anti-influenza A properties. After collection, the identification of each mushroom type was verified with internal transcribed spacer (ITS) gene sequencing using fungal-specific primers. Extracts were prepared by heating dried mushroom powder at 100℃ for 2 h. The cytotoxicity of the extracts was evaluated by MTT assay. The anti-influenza A properties of each extract were evaluated using the ASTM E1052-11 protocol, which is the international standardized approach. Results: The efficacy of the mushroom extracts against influenza A was evaluated using hot mushroom extract solutions, each of which had a concentration of 10 g powdered mushroom per liter of hot water. This ratio was selected as all of the mushrooms had little cytotoxic effect at this concentration. The influenza virus reduction titer of Pleurotus ostreatus was 5.519, with a virus removal efficacy of 99.999%. This was the highest antiviral efficacy among the 11 mushroom species. The virus inhibition titers of Phallus rubrovolvata and P. luteus were 4.477 and 2.247, respectively. Their virus inhibition efficacies were 99.997% and 99.433%, respectively. The efficacy of M. esculenta was 90.303%. The antiviral effects of Grifola% that of G. frondosawas 78.788%, and that of S. imbricatuswas 75.758%. The virus suppression efficacy of Tricholoma bakamatsutake and Pachyma hoelen were 66.667% and 63.636%, respectively. The extract solutions of the remaining three species (Sparassis latifolia, Amanita caesareoides, and Marasmius siccus) all showed a virus reduction efficacy of 60%. Conclusions: This study demonstrates the potential of mushroom extracts for medicinal use as antiviral treatments for influenza A infections.
... Breast cancer (mouse model) [139] In this review, we first summarize the currently known immune checkpoints and relevant FDA-approved blockades, briefly discuss ICI therapy-induced side effects, and then introduce representative phytochemicals along with their advantages and shortcomings in cancer treatment. Finally, we comment on combination therapies of immune checkpoint inhibitors with phytochemicals, with a focus on the future development of this novel anti-cancer therapy. ...
Article
Immune checkpoint inhibitor (ICI) therapy has dramatically changed cancer treatment, opening novel opportunities to cure malignant diseases. To date, most prevalently targeted immune checkpoints are programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), with many others being under extensive investigations. However, according to available data, only a fraction of patients may respond to ICI therapy. Additionally, this therapy may cause severe adverse immune-related side effects, such as diarrhea, headache, muscle weakness, rash, hepatitis and leucopenia, although most of them are not fatal, they can affect the patient's treatment outcome and quality of life. On the other hand, growing evidence has shown that phytochemicals with anticancer effects may combine ICI therapy to augment the safety and effectiveness of the treatment against cancer while reducing the adverse side effects. In this review, we summarize the state of art in the various experiments and clinical application of ICIs plus phytochemicals, with a focus on their combined use as a novel therapeutic strategy to cure cancer.
... Recently, numerous immune-based therapies have been established to be beneficial for the eradication of tumors in animal models. Primary immune organs, including the spleen and thymus, play vital roles in controlling the anti-tumor immunity [45]. The spleen is the principal peripheral lymphoid organ in the body and is the location of B and T cells. ...
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Background Use of natural products has been proposed as an efficient method in modulation of immune system and treatment of cancers. The aim of this study was to investigate the potential of cryptotanshinone (CPT), naringenin, and their combination in modulating the immune response towards Th1 cells and the involvement of JAK2/STAT3 signaling pathway in these effects. Methods Mouse models of delayed type hypersensitivity (DTH) were produced and treated with naringenin and CPT. The proliferation of spleen cells were assessed by Bromodeoxyuridine (BrdU) assay. Flowcytometry and enzyme-linked immunosorbent assay (ELISA) tests were employed to evaluate subpopulation of T-lymphocytes and the levels of cytokines, respectively. The JAK/STAT signaling pathway was analyzed by Western blotting. Results We showed higher DTH, increased lymphocyte proliferation, decreased tumor growth and reduced JAK2/STAT3 phosphorylation in mice treated with naringenin and CPT. Moreover, a significant decline in the production of IL-4 and an upsurge in the production of IFN-γ by splenocytes were observed. Additionally, the population of intra-tumor CD4 ⁺ CD25 ⁺ Foxp3 ⁺ T cells was significantly lower in naringenin + CPT treated animals than that in controls. Conclusion Naringenin-CPT combination could exert immunomodulatory effects, suggesting this combination as a novel complementary therapeutic regimen for breast cancer.
... [40][41][42][43][44][45][46][47][48] Many cancer studies have shown that cellular events such as invasion, migration, and metastasis in cancer are connected to primary causes of cancer-related deaths. 49,50 To 51 also showed that S. imbricatus aquaticus extract inhibited cell migration and invasion of 4T1 and MCF-7 cancer cells. Antitumor activity of polysaccharides from S. aspratus mycelium was also observed under in vitro cell culture conditions, and S. aspratus polysaccharides decreased cell vitality of different cancer cells such as HepG2, HeLa, A549, and L-02. ...
Article
Among natural products, mushrooms are well known for their nutritional value and health-improving features. In this study, the total phenolic content, total oxidant status, total antioxidant capacity, lipid hydroperox-ides, and total free sulfhydryl levels of wild edible mushroom Sarcodon squamosus were investigated. The agar disc diffusion method was applied to test the antimicrobial effect of S. squamosus methanolic extract against Gram-positive bacteria (Micrococcus luteus NCIBM, Staphylococcus aureus ATCC 25923, and Bacillus subtilis ATCC 6633), Gram-negative bacteria (Proteus vulgaris RSKK 96026, Escherichia coli ATCC 35218, and Yersinia enterocolitica RSKK 1501), and yeast (Candida albicans ATCC 10231). According to the obtained results, S. squamosus methanolic extract had strong antioxidant and antimicrobial activity. Antiproliferative effects of the time and dose of S. squamosus extract on human hepatocellular carcinoma HepG2 cells were determined with the XTT assay. The anti-invasive and apoptotic potential of the extract was evaluated with the Matrigel invasion chamber and TUNEL assays, respectively. S. squamosus extract also showed antiproliferative and anti-invasive activity and induced apoptosis in HepG2 hepato-cellular carcinoma cells in vitro. In conclusion, S. squamosus can be considered as both a functional food and a source of nutraceuticals.
... Tan et al. revealed that the Sarcodon imbricatus extract (SIE) effectively inhibited the growth, migration, and invasion properties of breast cancer cells in vitro and reduced tumour growth in vivo. Mechanically, SIE significantly increased serum concentrations of IL-2, IL-6, and TNF-α, as well as NK cell activity and the viability of splenocytes, while decreasing the expression of programmed cell death-ligand 1 (PD-L1) in 4T1 tumour-bearing mice [96]. ...
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Mycomedicine is a unique class of natural medicine that has been widely used in Asian countries for thousands of years. Modern mycomedicine consists of fruiting bodies, spores, or other tissues of medicinal fungi, as well as bioactive components extracted from them, including polysaccharides and, triterpenoids, etc. Since the discovery of the famous fungal extract, penicillin, by Alexander Fleming in the late 19th century, researchers have realised the significant antibiotic and other medicinal values of fungal extracts. As medicinal fungi and fungal metabolites can induce apoptosis or autophagy, enhance the immune response, and reduce metastatic potential, several types of mushrooms, such as Ganoderma lucidum and Grifola frondosa, have been extensively investigated, and anti-cancer drugs have been developed from their extracts. Although some studies have highlighted the anti-cancer properties of a single, specific mushroom, only limited reviews have summarised diverse medicinal fungi as mycomedicine. In this review, we not only list the structures and functions of pharmaceutically active components isolated from mycomedicine, but also summarise the mechanisms underlying the potent bioactivities of several representative mushrooms in the Kingdom Fungi against various types of tumour.
... Several worldwide studies have also demonstrated the anticancer activity of wild edible mushrooms. Tan et al. 34 found that aqueous extract of Sarcodon imbricatus inhibited breast cancer cells in vitro and reduced cell growth in vivo. Baek et al. 35 found that methanol extract of chaga (Inonotus obliquus) exhibited cytotoxic activity against human lung cancer cells. ...
Article
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... For example, Li et al. reported that polysaccharide LRP-1 purified from Leccinum rugosiceps inhibited the growth of human hepatoma cells HepG2 and human breast carcinoma MCF-7 cells, and induced the secretion of NO, IL-6 and TNF-α in vitro [151]. Similarly, a recent report showed that an aqueous extract of Sarcodon imbricatus (SIE) effectively inhibited the growth, migration, and invasion properties of breast cancer cells in vitro and reduced tumor growth in vivo, while showing increased expression of PD-L1 and increased NK cell viability [152]. Furthermore, Xue et al. reported that a triterpenoid EAe from Pleurotus eryngii inhibited MCF-7 cell lines proliferation with an EC50 of 298.26 µg/mL, and significantly inhibited the growth of CD-1 tumors (inhibition rate of 65%) in mice in a dose-dependent manner without toxicity [153]. ...
... For example, Li et al. reported that polysaccharide LRP-1 purified from Leccinum rugosiceps inhibited the growth of human hepatoma cells HepG2 and human breast carcinoma MCF-7 cells, and induced the secretion of NO, IL-6 and TNF-α in vitro [151]. Similarly, a recent report showed that an aqueous extract of Sarcodon imbricatus (SIE) effectively inhibited the growth, migration, and invasion properties of breast cancer cells in vitro and reduced tumor growth in vivo, while showing increased expression of PD-L1 and increased NK cell viability [152]. Furthermore, Xue et al. reported that a triterpenoid EAe from Pleurotus eryngii inhibited MCF-7 cell lines proliferation with an EC50 of 298.26 µg/mL, and significantly inhibited the growth of CD-1 tumors (inhibition rate of 65%) in mice in a dose-dependent manner without toxicity [153]. ...
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Mushrooms have been valued as food and health supplements by humans for centuries. They are rich in dietary fiber, essential amino acids, minerals, and many bioactive compounds, especially those related to human immune system functions. Mushrooms contain diverse immunoregulatory compounds such as terpenes and terpenoids, lectins, fungal immunomodulatory proteins (FIPs) and polysaccharides. The distributions of these compounds differ among mushroom species and their potent immune modulation activities vary depending on their core structures and fraction composition chemical modifications. Here we review the current status of clinical studies on immunomodulatory activities of mushrooms and mushroom products. The potential mechanisms for their activities both in vitro and in vivo were summarized. We describe the approaches that have been used in the development and application of bioactive compounds extracted from mushrooms. These developments have led to the commercialization of a large number of mushroom products. Finally, we discuss the problems in pharmacological applications of mushrooms and mushroom products and highlight a few areas that should be improved before immunomodulatory compounds from mushrooms can be widely used as therapeutic agents.
... Fischer induced apoptosis in multiple cell lines such as cervical HeLa, hepatoma HepG2, breast MCF-7 and osteosarcoma S180 [93][94][95]. Aqueous extract of Sarcodon imbricatus showed anticancer effects in MDA-MB-231, MDA-MB-468, MT-1, MCF-7 breast cancer cells and antitumor effects in 4T1 mouse breast cancer model by causing an increase in interleukin levels, tumor necrosis factor-α and the reduction of PD-L1 protein expressions [96]. ...
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Traditional Chinese Medicine, a long-established method for treating various types of cancers using various forms of herbal medicine has recently received the wide-acclaim for its beneficiary effects. Although the scientific proof for such medicine was limited several decades ago, recent research evidences have been supportive for this type of medicine. Chinese medicine can have several beneficial effects and the mechanistic studies in this aspect are the need of the hour. Therefore, the current manuscript is centered on effects of the herbal and mushroom formulations used in Chinese medicine on treating several cancers and the mechanisms involved. The authors of the manuscript suggest that apoptosis is one among the most probable mechanisms of anticancer effect of herbal and mushroom formulations used in Chinese medicine.
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Thousands of organisms fall under the umbrella of fungal species, many with unique properties; some innocuous, some useful and some harmful. This book covers the chemical composition and nutraceutical and pharmaceutical properties of edible fungi. It provides updates, future trends and perspectives on edible fungi, their nutritional properties, chemical features and different biological activities ascribed to them. Linking their functional use with different food products, it details the many health related properties of edible fungi. Phenolic acids, fatty acids, macromolecules, and different terpenes and steroids are presented as compounds with health improving properties. The book also discusses current technologies for mushroom cultivation and cultural use of mushrooms around the globe. Intended for food scientists and technologists, this book offers insights into current research and developments on edible fungi and will stimulate additional research in this area. It could also be considered as a supplementary text for courses such as applied or medical mycology.
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Mushrooms provide a reliable source of bioactive compounds and have numerous nutritional values, which is one of the reasons why they are widely used for culinary purposes. They may also be a remedy for several medical conditions, including cancer diseases. Given the constantly increasing number of cancer incidents, the great anticancer potential of mushrooms has unsurprisingly become an object of interest to researchers. Therefore, this review aimed to collect and summarize all the available scientific data on the anti-cancer activity of mushroom extracts. Our research showed that mushroom extracts from 92 species, prepared using 12 different solvents, could reduce the viability of 38 various cancers. Additionally, we evaluated different experimental models: in vitro (cell model), in vivo (mice and rat model, case studies and randomized controlled trials), and in silico. Breast cancer proved to be sensitive to the highest number of mushroom extracts. The curative mechanisms of the studied mushrooms consisted in: inhibition of cancer cell proliferation, unregulated proportion of cells in cell cycle phases, induction of autophagy and phagocytosis, improved response of the immune system, and induction of apoptotic death of cells via upregulation of pro-apoptotic factors and downregulation of anti-apoptotic genes. The processes mainly involved the expression of caspases -3, -8, -9, AKT, p27, p53, BAX, and BCL2. The quoted results could lead to the classification of mushrooms as nutraceuticals used to prevent a variety of disorders or to support treatment of cancer diseases.
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Ethnopharmacological relevance: The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint is one of the most promising therapeutic targets for cancer immunotherapy, but several challenges remain in current anti-PD-1/PD-L1 therapy. Natural products, mainly derived from traditional medicine, could improve and expand anti-PD-1/PD-L1 therapy because of their advantages such as large diversity and multi-target effects. Aim of the study: This review summarize natural products, raw extracts, and traditional medicines with pharmacological effects associated with the PD-1/PD-L1 axis, particularly PD-L1. Materials and methods: Electronic literature databases, including Web of Science, PubMed, and ScienceDirect, and online drugs and chemicals databases, including DrugBank, ZINC, PubChem, STITCH, and CTD, were searched without date limitation by February 2021. 'Natural product or herb or herbal plant or traditional medicine' and 'PD-L1' and 'Cancer immunotherapy' were used as the search keywords. Among 112 articles identified in database searching, 54 articles are full text articles, reporting in silico, in vitro, in vivo and clinical trials. 68 articles included are review articles and grey literature such as thesis and congress abstracts. Results: Several natural products and traditional medicines have exhibited diverse and multi-functional effects including direct blockade of PD-1/PD-L1 interactions, modulation of PD-L1 expression, and cooperation with PD-1/PD-L1 inhibitors. Conclusion: Natural products and traditional medicines can facilitate the development of more effective and acceptable diverse strategies for anti-PD-1/PD-L1 therapy, but further exploration of natural products and pharmaceutical techniques is required.
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Immune checkpoint proteins including programmed cell death protein 1 (PD-1), its ligand PD-L1 and cytotoxic T lymphocyte-associated antigen-4 (CTLA‐4) are involved in proliferation, angiogenesis, metastasis, chemoresistance via immune escape and immune tolerance by disturbing cytotoxic T cell activation. Though many clinical trials have been completed in several cancers by using immune checkpoint inhibitors alone or in combination with other agents to date, recently multi-target therapy is considered more attractive than monotherapy, since immune checkpoint proteins work with other components such as surrounding blood vessels, dendritic cells, fibroblasts, macrophages, platelets and extracellular matrix within tumor microenvironment. Thus, in the current review, we look back on research history of immune checkpoint proteins and discuss their associations with platelets or tumor cell induced platelet aggregation (TCIPA) and FOXP3+ regulatory T cells (Tregs) related molecules involved in immune evasion and tumor progression, clinical implications of completed trial results and signaling networks by phytochemicals for combination therapy with immune checkpoint inhibitors and suggest future research perspectives.
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Estimates of the worldwide incidence and mortality from 36 cancers and for all cancers combined for the year 2018 are now available in the GLOBOCAN 2018 database, compiled and disseminated by the International Agency for Research on Cancer (IARC). This paper reviews the sources and methods used in compiling the cancer statistics in 185 countries. The validity of the national estimates depends upon the representativeness of the source information, and to take into account possible sources of bias, uncertainty intervals are now provided for the estimated sex‐ and site‐specific all‐ages number of new cancer cases and cancer deaths. We briefly describe the key results globally and by world region. There were an estimated 18.1 million (95% UI: 17.5–18.7 million) new cases of cancer (17 million excluding non‐melanoma skin cancer) and 9.6 million (95% UI: 9.3–9.8 million) deaths from cancer (9.5 million excluding non‐melanoma skin cancer) worldwide in 2018.
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When pathogenic stresses are recognized by innate immune cells, inflammasomes are assembled and caspase-1 is activated, resulting in the conversion of pro-IL-18 into mature IL-18. Because natural killer (NK) cells express IL-18 receptors, IL-18 may play roles in immune functions of NK cells. In the present study, we examined the effect of IL-18 on NK cells derived from lung cancer patients and healthy adult volunteers. When peripheral blood NK cells were stimulated with IL-2, the cells formed clusters beginning on day 5-6 and proliferated thereafter, in which the number of NK cells increased by 10-fold in 10 days. When IL-18 was added, cell clusters were observed as early as on day 4 and NK cells proliferated vigorously. On day 10, the expansion rate was 56-fold on average, showing that IL-18 promoted the expansion of NK cells. It was also notable that IL-18 enhanced the expression of CD80, CD86, HLA-DR and HLA-DQ on NK cells, suggesting that IL-18 conferred NK cells an APC-like phenotype. When cellular cytotoxicity was determined, APC-like NK cells efficiently killed tumor cells and anti-tumor activity was augmented by the addition of tumor antigen-specific mAbs. In addition, IFN-γ was produced by APC-like NK cells in response to tumor cells, and the cytokine production was further enhanced by mAbs. Taken together, IL-18 not only promoted the expansion of NK cells, but also changed the phenotype of NK cells. IL-2/IL-18-induced NK cells might, therefore, serve as a bridge between innate immunity and adaptive immunity and be useful for cancer immunotherapy.
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The ability to non-invasively monitor tumor-infiltrating T cells in vivo could provide a powerful tool to visualize and quantify tumor immune infiltrates. For non-invasive evaluations in vivo, an anti-CD3 mAb was modified with desferrioxamine (DFO) and radiolabeled with zirconium-89 (Zr-89 or ⁸⁹Zr). Radiolabeled ⁸⁹Zr-DFO-anti-CD3 was tested for T cell detection using positron emission tomography (PET) in both healthy mice and mice bearing syngeneic bladder cancer BBN975. In vivo PET/CT and ex vivo biodistribution demonstrated preferential accumulation and visualization of tracer in the spleen, thymus, lymph nodes, and bone marrow. In tumor bearing mice, ⁸⁹Zr-DFO-anti-CD3 demonstrated an 11.5-fold increase in tumor-to-blood signal compared to isotype control. Immunological profiling demonstrated no significant change to total T cell count, but observed CD4⁺ T cell depletion and CD8⁺ T cell expansion to the central and effector memory. This was very encouraging since a high CD8+ to CD4+ T cell ratio has already been associated with better patient prognosis. Ultimately, this anti-CD3 mAb allowed for in vivo imaging of homeostatic T cell distribution, and more specifically tumor-infiltrating T cells. Future applications of this radiolabeled mAb against CD3 could include prediction and monitoring of patient response to immunotherapy.
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Diabetic patients have higher incidence and mortality of cancer. Recent study revealed that hyperglycemia-induced oxidative stress is involved in the acceleration of tumor metastasis. We used model of high dose streptozotocin-induced diabetes to investigate its effect on tumor growth and modulation of antitumor immune response of 4T1 murine breast cancer in BALB/c mice. Diabetes accelerated tumor appearance, growth and weight, which was associated with decreased NK cells cytotoxicity against 4T1 tumor cells in vitro. Diabetes reduced frequencies of systemic NKG2D+, perforin+, granzyme+, IFN-γ+ and IL-17+ NK cells, while increased level of PD-1 expression and production of IL-10 in NK cells. Diabetes decreased percentage of NKG2D+NK cells and increased percentage of PD-1+ NK cells also in primary tumor. Diabetes increased accumulation of IL-10+ Tregs and TGF-β+ myeloid derived suppressor cells (MDSCs) in spleen and tumor. Diabetic sera in vitro significantly increased percentage of KLRG-1+ and PD-1+ NK cells, decreased percentage of IFN-γ+NK cells, expression of NKp46 and production of perforin, granzyme, CD107a and IL-17 per NK cell in comparison to glucose added mouse sera and control sera. Significantly increased percentages of inducible nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO) producing MDSCs and dendritic cells (DC) were found in the spleens of diabetic mice prior to tumor induction. 1-methyl-DL-tryptophan, specific IDO inhibitor, almost completely restored phenotype of NK cells cultivated in diabetic sera. These findings indicate that diabetes promotes breast cancer growth at least in part through increased accumulation of immunosuppressive cells and IDO mediated attenuation of NK cells.
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Culturing 3D-expanded human placental-derived adherent stromal cells (ASCs) in the presence of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) transiently upregulated the secretion of numerous anti-proliferative, anti-angiogenic and pro-inflammatory cytokines. In a 3D-spheroid screening assay, conditioned medium from these induced-ASCs inhibited proliferation of cancer cell lines, including triple-negative breast cancer (TNBC) lines. In vitro co-culture studies of induced-ASCs with MDA-MB-231 human breast carcinoma cells, a model representing TNBC, supports a mechanism involving immunomodulation and angiogenesis inhibition. In vivo studies in nude mice showed that intramuscular administration of induced-ASCs halted MDA-MB-231 cell proliferation, and inhibited tumor progression and vascularization. Thirty percent of treated mice experienced complete tumor remission. Murine serum concentrations of the tumor-supporting cytokines Interleukin-6 (IL-6), Vascular endothelial growth factor (VEGF) and Granulocyte-colony stimulating factor (G-CSF) were lowered to naïve levels. A somatic mutation analysis identified numerous genes which could be screened in patients to increase a positive therapeutic outcome. Taken together, these results show that targeted changes in the secretion profile of ASCs may improve their therapeutic potential.
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Background: The receptors of Notch family play an important role in controlling the development, differentiation, and function of multiple cell types. The aim of this study is to investigate the role of Notch1 signaling upon immune suppression induced by melanoma cells. Methods: Melanoma cell line B16 cells were transfected by lentivirus containing mouse Notch1 gene or Notch1 shRNA to generate B16 cell line that highly or lowly expressed Notch1. Notch1 in anti-tumor immune response was comprehensively appraised in murine B16 melanoma tumor model in immunocompetent and immunodeficient mice. The ratios of CD3+CD8+ cytotoxic T cells, CD49b+NK cells, CD4+CD25+FoxP3+ Tregs and Gr1+CD11b+ MDSCs in tumor-DLN or spleen were examined by flow cytometry. After the co-culture of B16 cells and CD8+ T cells, the effects of Notch1 on the proliferation and activation of T cells were assessed by CCK8 assay, CFSE dilution and Chromium-release test. The mRNA expression and supernatant secretion of immunosuppressive cytokines, TGF-β1, VEGF, IL-10 and IFN-γ were measured by RT-PCR and ELISA, respectively. Results: Downregulation or overexpression of Notch1 in B16 melanoma cells inhibited or promoted tumor growth in immunocompetent mice, respectively. Notch1 expression in B16 melanoma cells inhibited the infiltration of CD8+ cytotoxic T lymphocytes and NK cells and reduced IFN-γ release in tumor tissue. It could also enhance B16 cell-mediated inhibition of T cell proliferation and activation, and upregulate PD-1 expression on CD4+ and CD8+ T cells. The percentage of CD4+CD25+FoxP3+ Tregs and Gr1+CD11b+MDSCs were significantly increased in tumor microenvironment, and all these were attributed to the upregulation of TGF-β1. Conclusion: These findings suggested that Notch1 signaling in B16 melanoma cells might inhibit antitumor immunity by upregulation of TGF-β1.
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How to overcome drug resistance and prevent tumor metastasis is key to the success of malignant tumor therapy. In this paper, ADH-1 peptide-modified liposomes (A-LP) have been successfully constructed for restoring chemosensitivity and suppressing cancer cell migration. With a particle size of about 90 nm, this functionalized nanocarrier was loaded with fluorescent probe or paclitaxel (PTX). Cellular uptake studies showed that A-LP facilitated the delivery of anticancer drug to tumor cells undergoing EMT. Interestingly, this nanocarrier enhanced chemosensitivity by assessing the cell activity using CCK-8 assay. Further, the results of Wound scratch assay and Transwell migration assay showed the inhibition effect of this nanocarrier on tumor cell migration. Moreover, this nanocarrier exhibited significant tumor-targeting ability and anti-tumor efficacy in vivo. Collectively, A-LP might be a novel targeted drug delivery system to enhance the efficacy of chemotherapy and prevent tumor metastasis.
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Breast cancer is the most common malignancy in women and a public health problem worldwide. Breast cancer is often accompanied by an inflammatory process characterized by the presence of proinflammatory cytokines such as tumor necrosis factor (TNF-α), which has important implications in the course of the disease. Inflammation has been described primarily as a favorable environment for tumor development. However, under certain conditions TNF-α can promote signals for activation, differentiation, survival or cell death, so the study of the variants of this cytokine, its receptors, the presence of polymorphisms and its implication in different phenotypes of breast cancer is necessary. Although the clinical application of TNF-α has been limited by its toxicity and side effects, preclinical and clinical studies have shown that these effects may partially be avoided via tumor-targeted delivery strategies. In this manner, TNF-α alone or combined with chemotherapy and radiotherapy can function as an adjuvant in the treatment of breast cancer.
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The mushroom Ganoderma lucidum (G. lucidum) has been used for centuries in Asian countries to treat various diseases and to promote health and longevity. Clinical studies have shown beneficial effects of G. lucidum as an alternative adjuvant therapy in cancer patients without obvious toxicity. G. lucidum polysaccharides (GLP) is the main bioactive component in the water soluble extracts of this mushroom. Evidence from in vitro and in vivo studies has demonstrated that GLP possesses potential anticancer activity through immunomodulatory, anti-proliferative, pro-apoptotic, anti-metastatic and anti-angiogenic effects. Here, we briefly summarize these anticancer effects of GLP and the underlying mechanisms.
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Purpose of review: The purpose of the review is to summarize the data regarding PD-L1 expression in breast cancer and the results of first clinical trials with PD-1 or PD-L1 inhibitors in patients with metastatic breast cancer. Recent findings: PD-L1 expression is heterogeneous across primary breast cancers, and is generally associated with the presence of tumor-infiltrating lymphocytes and the presence of poor-prognosis features such as high grade, and aggressive molecular subtypes (triple-negative (TN), basal, HER2-enriched). Early phase clinical trials using PD-1 or PD-L1 inhibitors alone or in combination have shown objective tumor responses and durable long-term disease control, in heavily pre-treated patients, notably in the TN subtype. Blockade of PD-1 or PD-L1 shows impressive antitumor activity in some subsets of breast cancer patients. Many clinical trials are ongoing in the metastatic and neoadjuvant setting, alone and in combination with chemotherapy, targeted therapy, radiotherapy, and/or other immune therapy. The identification of biomarkers predictive for a clinical benefit is warranted.
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Metastasis causes approximately 90% of breast cancer-related deaths in women. Previously, we have demonstrated that 2-dodecyl-6-methoxycyclohexa-2,5-diene- 1,4-dione (DMDD) remarkably inhibited the growth of human breast cancer cells with little toxicity. In this study, we investigated the toxicity and efficacy of DMDD to treat metastatic breast tumors using an in vivo mouse model of the 4T1 mammary carcinoma. DMDD caused no observable toxicity and significantly extended the survival of 4T1 tumor-bearing mice. DMDD effectively inhibited the growth of 4T1 cells in vitro, and suppressed the growth and metastasis of mammary tumor in vivo. The levels of inflammatory cytokines in the serum (TNF-α, IL-6, IL-12, TGF-β, and VEGF) were down regulated by DMDD. Immunohistochemical analysis demonstrated that the inhibition of tumor growth and metastasis was associated with activation of Bax, cleaved caspases-3 and -9, and down-regulation of Bcl-2, MMP-2 and -9, NF-κB and IκBα. We speculate that DMDD inhibits cytokine production in the tumor cells in mice, which leads to deactivation of NF-κB pathway, and consequently inhibits the expression of many anti-apoptosis and metastasis-promoting genes, such as Bcl-2 and MMPs. Collectively, our results demonstrate the potential of DMDD as a safe and effective antitumor agent in the treatment of late-stage breast cancer.
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Adriamycin is a first-line chemotherapy agent against cancer, but the development of resistance has become a major problem. Although autophagy is considered to be an adaptive survival response in response to chemotherapy and may be associated with chemoresistance, its inducer and the underlying molecular mechanisms remain unclear. Here, we demonstrate that adriamycin up-regulates the both levels of TRPC5 and autophagy, and the increase in autophagy is mediated by TRPC5 in breast cancer cells. Blockade of TRPC5 or autophagy increased the sensitivity to chemotherapy in vitro and in vivo. Notably, we revealed a positive correlation between TRPC5 and the autophagy-associated protein LC3 in paired patients with or without anthracycline-taxane-based chemotherapy. Furthermore, pharmacological inhibition and gene-silencing showed that the cytoprotective autophagy mediated by TRPC5 during adriamycin treatment is dependent on the CaMKKβ/AMPKα/mTOR pathway. Moreover, adriamycin-resistant MCF-7/ADM cells maintained a high basal level of autophagy, and silencing of TRPC5 and inhibition of autophagy counteracted the resistance to adriamycin. Thus, our results revealed a novel role of TRPC5 as an inducer of autophagy, and this suggests a novel mechanism of drug resistance in chemotherapy for breast cancer.
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Human triple negative breast cancer (TNBC) is an aggressive disease, associated with a high rate of recurrence and metastasis. Current therapeutics for TNBC are limited, highly toxic and show inconsistent efficacy due to a high degree of intra-tumoral and inter-tumoral heterogeneity. Oncolytic viruses (OVs) are an emerging treatment option for cancers. Several OVs are currently under investigation in preclinical and clinical settings. Here, we examine the oncolytic potential of two tanapoxvirus (TPV) recombinants expressing mouse monocyte chemoattractant protein (mMCP)-1 [also known as mCCL2] and mouse interleukin (mIL)-2, in human TNBC, in vitro and in vivo. Both wild-type (wt) TPV and TPV recombinants demonstrated efficient replicability in human TNBC cells and killed cancer cell efficiently in a dose-dependent manner in vitro. TPV/∆66R/mCCL2 and TPV/∆66R/mIL-2 expressing mCCL2 and mIL-2, respectively, suppressed the growth of MDA-MB-231 tumor xenografts in nude mice significantly, as compared to the mock-injected tumors. Histological analysis of tumors showed areas of viable tumor cells, necrotic foci and immune cell accumulation in virus-treated tumors. Moreover, TPV/∆66R/mIL-2-treated tumors showed a deep infiltration of mononuclear immune cells into the tumor capsule and focal cell death in tumors. In conclusion, TPV recombinants expressing mCCL2 and mIL-2 showed a significant therapeutic effect in MDA-MB-231 tumor xenografts, in nude mice through induction of potent antitumor immune responses. Considering the oncolytic potency of armed oncolytic TPV recombinants expressing mCCL2 and mIL-2 in an experimental nude mouse model, these viruses merit further investigation as alternative treatment options for human breast cancer.
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Aims: Sarcodon imbricatus, an edible fungus, is widely used in Asian medicine because of its significant pharmacological activities. In the present study, we investigated the immunomodulatory effects of polysaccharide-enriched S. imbricatus extracts (SP) in cyclophosphamide (CTX)-induced immunosuppressed mice. Results: Astragalus polysaccharide (AP) was used as a positive control. Compared with CTX-induced immunosuppressed mice, thirty-day SP treatment strongly enhanced the organ indexes of spleen and thymus and suppressed hind paw swelling. Both AP and SP increased the serum levels of immunoglobulin (IgA, IgG, and IgM), and suppressed the overproduction of interleukin-2 (IL-2). Moreover, SP reduced methane dicarboxylic aldehyde levels, and increased the total antioxidant capacity, superoxide dismutase, and glutathione peroxidase in both serum and liver tissues of CTX-induced immunosuppressed mice. Conclusion: S. imbricatus extracts significantly improved immune function in CTX-induced immunosuppressed mice via modulation of oxidative systems.
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Medicinal mushrooms in recent years have been the subject of many experiments searching for anticancer properties. We previously screened thirteen mushrooms for their potential in inhibiting tumor growth, and found that the water extract of Amauroderma rude exerted the highest activity. Previous studies have shown that the polysaccharides contained in the water extract were responsible for the anticancer properties. This study was designed to explore the potential effects of the polysaccharides on immune regulation and tumor growth. Using the crude Amauroderma rude extract, in vitro experiments showed that the capacities of spleen lymphocytes, macrophages, and natural killer cells were all increased. In vivo experiments showed that the extract increased macrophage metabolism, lymphocyte proliferation, and antibody production. In addition, the partially purified product stimulated the secretion of cytokines in vitro, and in vivo. Overall, the extract decreased tumor growth rates. Lastly, the active compound was purified and identified as polysaccharide F212. Most importantly, the purified polysaccharide had the highest activity in increasing lymphocyte proliferation. In summary, this molecule may serve as a lead compound for drug development.
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Microorganisms can colonize a wide variety of medical devices, putting patients in risk for local and systemic infectious complications, including local-site infections, catheter-related bloodstream infections, and endocarditis. These microorganisms are able to grow adhered to almost every surface, forming architecturally complex communities termed biofilms. The use of natural products has been extremely successful in the discovery of new medicine, and mushrooms could be a source of natural antimicrobials. The present study reports the capacity of wild mushroom extracts to inhibit in vitro biofilm formation by multi-resistant bacteria. Four Gram-negative bacteria biofilm producers (Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, and Acinetobacter baumannii) isolated from urine were used to verify the activity of Russula delica, Fistulina hepatica, Mycena rosea, Leucopaxilus giganteus, and Lepista nuda extracts. The results obtained showed that all tested mushroom extracts presented some extent of inhibition of biofilm production. OPEN ACCESS Pathogens 2014, 3 668 Pseudomonas aeruginosa was the microorganism with the highest capacity of biofilm production, being also the most susceptible to the extracts inhibition capacity (equal or higher than 50%). Among the five tested extracts against E. coli, Leucopaxillus giganteus (47.8%) and Mycenas rosea (44.8%) presented the highest inhibition of biofilm formation. The extracts exhibiting the highest inhibitory effect upon P. mirabilis biofilm formation were Sarcodon imbricatus (45.4%) and Russula delica (53.1%). Acinetobacter baumannii was the microorganism with the lowest susceptibility to mushroom extracts inhibitory effect on biofilm production (highest inhibition—almost 29%, by Russula delica extract). This is a pioneer study since, as far as we know, there are no reports on the inhibition of biofilm production by the studied mushroom extracts and in particular against multi-resistant clinical isolates; nevertheless, other studies are required to elucidate the mechanism of action.
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This trial was performed to study the use of the mushroom Agaricus brasiliensis as an alternative additive to antimicrobial growth promoters in broiler chicken diets and to assess the quality of the broiler chicken breast meat of birds that are fed diets containing this fungus. Thus, 595 1-day-old chicks were reared in reused poultry litter without anticoccidial and antimicrobial additives. The results showed that a concentration of 1.6 g mushrooms/kg diet was ideal for these birds because it provided better bird performance. When the birds' immune system organs were analyzed, it was found that the addition of both mushrooms influenced the immune system organs of these broiler chickens. Adding A. brasiliensis to broiler chicken diets did not compromise breast meat quality.
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Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped into several protein families that are referred to as tumor necrosis factors, interleukins, interferons, and colony-stimulating factors. In recent years, it has become clear that some of these proteins as well as their receptors are produced in the organisms under physiological and pathological conditions. The exact initiation process of breast cancer is unknown, although several hypotheses have emerged. Inflammation has been proposed as an important player in tumor initiation, promotion, angiogenesis, and metastasis, all phenomena in which cytokines are prominent players. The data here suggest that cytokines play an important role in the regulation of both induction and protection in breast cancer. This knowledge could be fundamental for the proposal of new therapeutic approaches to particularly breast cancer and other cancer-related disorders.
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More and more medicinal mushrooms have been widely used as a miraculous herb for health promotion, especially by cancer patients. Here we report screening thirteen mushrooms for anti-cancer cell activities in eleven different cell lines. Of the herbal products tested, we found that the extract of Amauroderma rude exerted the highest activity in killing most of these cancer cell lines. Amauroderma rude is a fungus belonging to the Ganodermataceae family. The Amauroderma genus contains approximately 30 species widespread throughout the tropical areas. Since the biological function of Amauroderma rude is unknown, we examined its anti-cancer effect on breast carcinoma cell lines. We compared the anti-cancer activity of Amauroderma rude and Ganoderma lucidum, the most well-known medicinal mushrooms with anti-cancer activity and found that Amauroderma rude had significantly higher activity in killing cancer cells than Ganoderma lucidum. We then examined the effect of Amauroderma rude on breast cancer cells and found that at low concentrations, Amauroderma rude could inhibit cancer cell survival and induce apoptosis. Treated cancer cells also formed fewer and smaller colonies than the untreated cells. When nude mice bearing tumors were injected with Amauroderma rude extract, the tumors grew at a slower rate than the control. Examination of these tumors revealed extensive cell death, decreased proliferation rate as stained by Ki67, and increased apoptosis as stained by TUNEL. Suppression of c-myc expression appeared to be associated with these effects. Taken together, Amauroderma rude represented a powerful medicinal mushroom with anti-cancer activities.
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The antioxidant activities of the methanol extract of Sarcodon imbricatum wildly grown in the Black Sea Region of Turkey were investigated in this study. Antioxidant activities were evaluated in terms of total antioxidant activity, reducing power, metal chelating ability, inhibition of linoleic acid peroxidation, superoxide, peroxide and hydrogen peroxide scavenging effects. Various antioxidant activities were compared to references antioxidants such as alpha-tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and trolox. In total antioxidant (12674.45 mumol alpha-tocopherol/g of extract), superoxide scavenging (53.74%) and peroxide scavenging activity (45.73%), the methanol extract of Sarcodon imbricatum showed stronger activity patterns than that of references antioxidants. Reducing power, metal chelating activity and free radical (DPPH(*)) scavenging activity was increased with the increasing concentration. The contents of total phenolic, flavonoid, anthocyanin, ascorbic acid, beta-carotene and lycopene of Sarcodon imbricatum were determined and found to be noteworthy.
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Background: Increasing amount of evidence points to the importance of immunity in breast cancer. The prognostic value of cytokines and their effect on tumorigenesis remains inconsistent. Aim: To investigate the prognostic significance of IL6 and IL8 and their association with ER and HER2 in estrogen-dependent (ER+) breast cancer. Material and methods: The study included 79 premenopausal women with early and locally advanced ER+ breast cancer. All patients received adjuvant hormonal therapy: tamoxifen alone (56/79) or combination with LHRH agonist goserelin (23/79). IL6 and IL8 serum protein levels were measured by ELISA. Cox proportional hazards regression analysis was implemented for prognostic evaluation of the data categorized based on metastasis outcome. Results: IL6 associated with good (P = 0.001, HR = 0.05) and IL8 with poor disease outcome (P = 0.03, HR = 2.5) in the whole group of patients. Multivariate analyses highlighted IL6 as the independent prognostic factor (P = 0.001, HR = 0.0007). When patients were classified according to ER or HER2 status, IL6 did not have prognostic significance in ERlowand ERhighsubgroups, while IL8 retained prognostic significance only in the ERhighsubgroup (P = 0.04, HR = 2.8). IL6 was significant in both HER2- (P = 0.001, HR = 0.05) and HER2+ subgroups (P = 0.002, HR = 0.04), while IL8 retained its prognostic significance only in the HER2+ subgroup (P = 0.001, HR = 77.8). Conclusions: This study contributes to the clarification of the prognostic performance of IL6 and IL8 by providing their first prognostic evaluation in the homogenized ER+ breast cancer patient group. IL6 was indicated as a marker of favorable, whereas IL8 was a marker of unfavorable disease outcome.
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In this study, chemical properties of polysaccharides from rhizomes of Panax japonicus C. A. Mey (PSPJ) were investigated and the antitumor immunostimulatory activity of PSPJ was assessed in mice bearing H22 hepatoma cells. Chemical properties of PSPJ were determined by GC, FT-IR, 1H NMR and 13C NMR analysis. Furthermore, we showed that PSPJ repressed H22 tumor growth in vivo with undetectable toxic effects on tumor-bearing mice. PSPJ upregulated host thymus/spleen indexes and ConA/LPS-induced splenocyte proliferation. Cytotoxic activities of natural killer and CD8+ T cells against H22 hepatoma cells were also elevated. Tumor transplantation led to substantial apoptosis of CD4+ T cells and dysregulation of the cytokine profile secreted by CD4+ T cells. These abnormalities were alleviated by PSPJ in a dose-dependent manner. In tumor-associated macrophages (TAMs), PSPJ reduced the production of immunosuppressive factors such as TGF-β, IL-10 and PEG2. In addition, M2-like polarization of TAMs was also considerably declined in response to PSPJ. Our findings clearly demonstrated the antitumor immunostimulatory activity of PSPJ and supported considering PSPJ as an adjuvant reagent in clinical treatment of malignant diseases.
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To better understand the medicinal and nutritional value of mushrooms, we studied the fatty acid (FA) compositions and DPPH scavenging abilities of 11 mushrooms from Southwest China. The crude fat (CF) contents were examined initially, then 3 methods of FA methyl esterification were compared to identify which acid treatment was the most appropriate method. Then methyl esterification methods for 12 CFs were performed with acid treatment and the FA compositions were analyzed with gas chromatography-mass spectrometry. The results showed that tetradecanoic acid (14:0), hexadecenoic acid (16:1), hexadecanoic acid (16:0), heptadecanoic acid (17:0), octadecadienoic acid (18:2), octadecenoic acid (18:1), octadecanoic acid (18:0), docosanoic acid (22:0), and tetracosanoic acid (24:0) were detected in all the samples, with large amounts of hexadecanoic acid (16:0), octadecadienoic acid (18:2), octadecenoic acid (18:1), and octadecanoic acid (18:0). Daldinia eschscholtzii and Sarcodon imbricatus had the highest ratio value of unsaturated FAs to saturated FAs (4.33 and 3.03, respectively). The DPPH scavenging ability of 12 CFs was also tested. The free radical scavenging rates of the CFs were almost < 10% at a concentration of 0.10 mg/mL, except that of S. imbricatus, which reached 81.25%, with a half-maximal inhibitory concentration of 0.054 mg/mL. This strong DPPH free radical scavenging ability of S. imbricatus may be related to α-hydroxy FA.
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Mushrooms have been used extensively, owing to their nutritional and medicinal value, for thousands of years. Modern research confirms the therapeutic effect of traditionally used species. Inflammation is a natural response of the immune system to damaging factors, e.g. physical, chemical and pathogenic. Deficiencies of antioxidants, vitamins, and microelements, as well as physiological processes, such as aging, can affect the body’s ability to resolve inflammation. Mushrooms are rich in anti-inflammatory components, such as polysaccharides, phenolic and indolic compounds, mycosteroids, fatty acids, carotenoids, vitamins, and biometals. Metabolites from mushrooms of the Basidiomycota taxon possess antioxidant, anticancer, and most significantly, anti-inflammatory properties. Recent reports indicate that edible mushroom extracts exhibit favourable therapeutic and health-promoting benefits, particularly in relation to diseases associated with inflammation. In all certainty, edible mushrooms can be referred to as a “superfood” and are recommended as a valuable constituent of the daily diet.
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Therapy that targets programmed death 1 or programmed death 1 ligand 1 (PD-1/PD-L1), which are known as immune checkpoints, has been recently rapidly developing as oncotherapy for various carcinomas. However, this therapy has a poor effect on the treatment of pancreatic cancer with PD-1/PD-L1 blockade monotherapy. In this review, the development and limitations of anti-PD-1/PD-L1 monotherapy in pancreatic cancer are discussed. We then consider the underlying mechanism of anti-PD-1/PD-L1 monotherapy failure, combination strategies overcoming resistance to anti-PD-1/PD-L1 immunotherapy and the prospect of targeting PD-1/PD-L1 for the immunotherapy of pancreatic cancer.
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The precise role of interleukin (IL)-10 in breast cancer is not clear. Previous studies suggested a tumor-promoting role of IL-10 in breast cancer, whereas recent discoveries that IL-10 activated and expanded tumor-resident CD8⁺ T cells challenged the traditional view. Here, we investigated the role of IL-10 in HLA-A2-positive breast cancer patients with Grade III, Stage IIA or IIB in-situ and invasive ductal carcinoma, and compared it with that of IL-2, the canonical CD8⁺ T cell growth factor. We first observed that breast cancer patients presented higher serum levels of IL-2 and IL-10 than healthy controls. Upon prolonged TCR stimulation, peripheral blood CD8⁺ T cells from breast cancer patients tended to undergo apoptosis, which could be prevented by the addition of IL-2 and/or IL-10. The cytotoxicity of TCR-activated CD8⁺ T cells was also enhanced by exogenous IL-2 and/or IL-10. Interestingly, IL-2 and IL-10 demonstrated synergistic effects, since the enhancement in CD8⁺ T cell function when both cytokines were added was greater than the sum of the improvements mediated by each individual cytokine. IL-10 by itself could not promote the proliferation of CD8⁺ T cells but could significantly enhance IL-2-mediated promotion of CD8⁺ T cell proliferation. In addition, the cytotoxicity of tumor-infiltrating CD8⁺ T cells in breast tumor was elevated when both IL-2 and IL-10 were present but not when either one was absent. This synergistic effect was stopped by CD4⁺CD25⁺ regulatory T cells (Treg), which depleted IL-2 in a cell number-dependent manner. Together, these results demonstrated that IL-2 and IL-10 could work synergistically to improve the survival, proliferation, and cytotoxicity of activated CD8⁺ T cells, an effect suppressible by CD4⁺CD25⁺ Treg cells.
Article
Cyclophosphamide (CY) is a DNA alkylating agent, which is widely used with other chemotherapy drugs in the treatment of various types of cancer. It can be used not only as a chemotherapeutic but also as an immunomodulatory agent to inhibit IL-10 expression and T regulatory cells (Tregs). Fibroblast activation protein α (FAPα) is expressed in cancer-associated fibroblasts in the tumor microenvironment. Immunotherapy based on FAPα, as a tumor stromal antigen, typically induces specific immune response targeting the tumor microenvironment. This study evaluated the efficacy of a previously unreported CY combination strategy to enhance the limited anti-tumor effect of a DNA vaccine targeting FAPα. The results suggested CY administration could promote the percentage of splenic CD8(+ )T cells and decrease the proportion of CD4 (+) CD25 (+) Foxp3(+ )Tregs in spleen. In tumor tissues, levels of immunosuppressive cytokines including IL-10 and CXCL-12 were also reduced. Meanwhile, the CY combination did not impair the FAPα-specific immunity induced by the DNA vaccine and further reduced tumor stromal factors. Most importantly, FAP-vaccinated mice also treated with CY chemotherapy showed a marked suppression of tumor growth (inhibition ratio =80%) and a prolongation of survival time. Thus, the combination of FAPα immunotherapy and chemotherapy with CY offers new insights into improving cancer therapies.
Article
A novel neutral polysaccharide (LGPS-1), with a molecular weight of 1.547 × 10⁵ Da, was isolated from Lentinus giganteus by precipitation and purification. The monosaccharides included d-mannose (Man), d-glucose (Glc) and d-galactose (Gal) with a molar ratio of 3.0:4.1:7.1. The backbone of LGPS-1 was composed of 1,6-Galp and 1,3,6-Manp whereas the branches were composed of 1,6-Glcp and 1-Glcp. The anticancer efficacy of LGPS-1 was assessed using HepG2 hepatocellular carcinoma cells. The results showed that LGPS-1 inhibited the proliferation of HepG2 cells and also induced the activation of caspase-3, and cleavage of PARP-1. Western blot analysis revealed that LGSP-1 significantly induced a loss of mitochondrial membrane potential (Δym), increased the ratio of Bax/Bcl-2, promoted the release of cytochrome c into cytoplasm as well as inhibited the phosphorylation of Akt in HepG2 cells. These findings suggest that LGPS-1 induced apoptosis in HepG2 cells through intrinsic mitochondrial apoptosis and PI3K/Akt signaling pathways.
Article
Importance The development of programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) checkpoint inhibitors has changed the landscape of non–small-cell lung cancer (NSCLC) therapy, with 2 approvals from the US Food and Drug Administration of PD-1 inhibitors for second-line therapy. However, the rational use of these agents has been limited by the lack of a definitive predictive biomarker. Observations Tumor PD-L1 expression is associated with an increased likelihood of NSCLC response to these agents, although responses can still occur at a low rate in PD-L1–negative tumors. The use of PD-L1 as a predictive biomarker for use of PD-1/PD-L1 inhibitors is limited by the multitude of PD-L1 antibodies, assays, scoring systems, and thresholds for positivity currently used. Alternative biomarkers such as tumor neoantigens identified through whole-exome sequencing and clinical parameters (eg, smoking or oncogene driver status) may also have predictive value. Biomarkers that can direct the rational use of PD-1/PD-L1 checkpoint inhibitors are crucial given the risk of life-threatening immune-related complications associated with these therapies and the reality that most patients still do not benefit from their use. Conclusions and Relevance The refinement of existing biomarkers and identification of novel predictive biomarkers will be key to ensuring the effective and safe use of these agents. Since most patients still do not benefit from these agents, it is critical to continue to work to define the select patient population who will derive durable benefit from PD-1/PD-L1 inhibition and identify markers that could have predictive value for combination therapies that could expand the population who benefit.
Article
Estrogen receptor (ER) is required for carcinoma cell proliferation in the great majority of breast cancer and also functions as a dimer. ER dimeric proteins have been largely identified by BRET/FRET analyses but their in situ visualization have not yet been reported. Recently, in situ Proximity Ligation Assay (PLA) has been developed as the methods detecting protein interactions in situ. Therefore, in this study we firstly demonstrated the dimerization of ERα in breast carcinoma cell lines and tissues using PLA. The human breast carcinoma cell lines MCF-7, T-47D and MDA-MB-231 were used in this study. Cells were treated with ER agonist or antagonist and fixed in 4% PFA, and ER dimers were subsequently detected using PLA. The evaluation of ER dimers in breast carcinoma cell lines were quantified by measuring the area of dots localized in the nuclei using image analysis. We also firstly demonstrated the visualization of ER dimer patterns in 10% formalin-fixed paraffin-embedded tissues of breast cancer using PLA technique. Estradiol (E2) administration induced ERα homodimers in the nuclei of MCF-7 and T-47D but not in ER-negative MDA-MB-231. 4-OH tamoxifen also induced ERα homodimers but the subcellular localization of these ERα homodimers was predominant in cytoplasm instead of the nuclei induced by E2 treatment. ICI182,780 treatment did decrease the number of formation of ERα homodimers in MCF-7. In breast cancer patients, ERα PLA score was significantly correlated positively with ERα- or PgR (progesterone receptor) immunohistochemical scores and inversely with Ki-67-labeling index, respectively. We also demonstrated the ERα/β heterodimer as well as ERα homodimers in both breast carcinoma cell lines and surgical pathology specimens. In summary, we did firstly succeed in the visualization of ER dimeric proteins using PLA method. The evaluation of ER dimer patterns could provide pivotal information as to the prediction of response to endocrine therapy of breast cancer patients.
Article
Mesenchymal stem cells from human adipose tissue (hASCs) are proposed as suitable tools for soft tissue engineering and reconstruction. Although it is known that hASCs have the ability to home to sites of inflammation and tumor niche, the role of inflammatory cytokines in the hASCs-affected tumor development is not understood. We found that interferon-γ (IFN-γ) and/or tumor necrosis factor-α (TNF-α) prime hASCs to produce soluble factors which enhance MCF-7 cell line malignancy in vitro. IFN-γ and/or TNF-α-primed hASCs produced conditioned media (CM) which induced epithelial to mesenchymal transition (EMT) of MCF-7 cells by reducing E-Cadherin and increasing Vimentin expression. Induced EMT was accompanied by increased invasion, migration, and urokinase type-plasminogen activator (uPA) expression in MCF-7 cells. These effects were mediated by increased expression of transforming growth factor-β1(TGF-β1) in cytokines-primed hASCs, since inhibition of type I TGF-β1 receptor on MCF-7 cells and neutralization of TGF-β1 disabled the CM from primed hASCs to increase EMT, cell migration, and uPA expression in MCF-7 cells. Obtained data suggested that IFN-γ and/or TNF-α primed hASCs might enhance the malignancy of MCF-7 cell line by inducing EMT, cell motility and uPA expression in these cells via TGF-β1-Smad3 signalization, with potentially important implications in breast cancer progression.
Article
Natural killer (NK) cells are the prototype innate lymphoid cells endowed with potent cytolytic function that provide host defence against microbial infection and tumours. Here, we review evidence for the role of NK cells in immune surveillance against cancer and highlight new therapeutic approaches for targeting NK cells in the treatment of cancer.
Article
In this study, one polysaccharide (GFP1), with an average molecular weight of 1.4×10(5)Da, was isolated from Ginseng fruits. GFP1 was composed of galactose, glucose, rhamnose, and arabinose in a molar ratio of 6.1:2.0:1.1:3.2, and had a backbone mainly consisting of (1→6)-linked-Galp, (1→3,6)-linked-Galp and (1→3,6)-linked-Glcp residues, which was terminated with terminal (1→)-linked-Araf or -Rhap attached to O-3 position of (1→3,6)-linked-Galp and (1→3,6)-linked-Glcp. We also evaluated the effect of GFP1 on anti-tumor immune response in Lewis lung carcinoma (LLC)-bearing mouse model and explored the possible mechanism. GPF1 could significantly inhibit tumor growth and lung metastasis in vivo, increase the relative spleen and thymus weight, promote ConA or LPS-induced spleen lymphocytes proliferation, elevate the activities of NK cell in spleen, and increase the serum concentration of interleukin-2 (IL-2) and interferon-γ (IFN-γ), as well as the ratio of CD4(+)/CD8(+) in LLC-bearing mice. All these findings implied that GFP1 could effectively inhibit tumor growth and lung metastasis via activating immune function and provide insights into the mechanism of GFP1 in the prevention and treatment of lung cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
Breast cancer is the most common malignancy in women. Interleukin-2 (IL-2) plays a key role in the proliferation of T cells and natural killer cells. It has been reported that polymorphisms in the IL-2 gene are associated with various cancers. The aim of this study was to examine the effect of polymorphisms in the IL-2 gene on the development of breast cancer in Chinese population. IL-2-330T/G and +114T/G polymorphisms were assessed in 638 breast cancer cases and 682 age-matched healthy controls. Data were analyzed using the Chi-square test. Results showed that individuals with -330TG genotype and -330GG genotype had significantly increased susceptibility to breast cancer (Odds ratio [OR]=1.42, 95% confidence interval [CI]: 1.10-1.79, p=0.0021 and OR=2.26, 95%CI: 1.53-3.30, p<0.0001). The +114T/G polymorphism did not show any correlation with breast cancer. In addition, when analyzing the survival time of breast cancer patients with IL-2-330T/G polymorphism, cases with -330G allele had significantly shorter survival time compared with wild-type patients (p=0.002). These results suggested that polymorphism in the IL-2 gene was associated with increased susceptibility to breast cancer and could be used as a prognostic marker for this malignancy.
Article
The effects of processing and cooking practices on the chemical composition and antioxidant activity of Portuguese wild edible mushroom species (Lactarius deliciosus, Macrolepiota mastoidea, Macrolepiota procera, and Sarcodon imbricatus) were investigated. Dried, frozen, and cooked samples were analyzed for proximate constituents (moisture, fat, crude protein, ash, and carbohydrates) and nutritional value. Fatty acid and sugar profiles were also obtained by gas-liquid chromatography/flame ionization detection and high-performance liquid chromatography/refraction index, respectively. The antioxidant properties were evaluated by several biochemical assays: 2,2-diphenyl-1-picrylhydrazyl radical scavenging capacity, reducing power, inhibition of beta-carotene bleaching, and inhibition of lipid peroxidation in brain tissue using thiobarbituric acid reactive substances. Results of this study show that mushroom species and processing and cooking practices are all effective determinants for either chemical composition or antioxidant properties. Cooked samples proved to have lower nutrient concentrations and lower antioxidant activities than either dried or frozen samples. In what concerns fatty acids and sugar individual profiles, only cooking proved to be relevant: The cooked samples presented higher monounsaturated fatty acid and lower polyunsaturated fatty acid and sugars contents.